Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer's disease.

Abstract

The synthesis, biological evaluation and molecular modeling of new multipotent inhibitors of type I and type II, able to simultaneously inhibit monoamine oxidases (MAO) as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), is described. Compounds of type I were prepared by sequential reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (14) [or 2,6-dichloropyridine-3,5-dicarbonitrile (15)] with prop-2-yn-1-amine (or N-methylprop-2-yn-1-amine) and 2-(1-benzyl-piperidin-4-yl)alkylamines 22-25. Compounds of type II were prepared by Friedländer type reaction of 6-amino-5-formyl-2-(methyl(prop-2-yn-1-yl)amino)nicotinonitriles 32 and 33 with 4-(1-benzylpiperidin-4-yl)butan-2-one (31). The biological evaluation of molecules 1-11 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO-A and MAO-B inhibition. Kinetic studies of compound 8 proved that this is a EeAChE mixed type inhibitor (IC(50) = 16 ± 2; Ki = 12 ± 3 nM). Molecular modeling investigation on compound 8 confirmed its dual AChE inhibitory profile, binding simultaneously at the catalytic active site (CAS) and at the peripheric anionic site (PAS). In overall, compound 11, as a potent and selective dual AChEI, showing a moderate and selective MAO-A inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer's disease.

• Authors: Abdelouahid Samadi, Mourad Chioua, Irene Bolea, Cristóbal de Los Ríos, Isabel Iriepa, Ignacio Moraleda, Agatha Bastida, Gerard Esteban, Mercedes Unzeta, Enrique Gálvez, José Marco-Contelles
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 46 Issue 9 Pg. 4665-8 (Sep 2011) ISSN: 1768-3254 [Electronic] France
• PMID: 21669479 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Chemical References

• Cholinesterase Inhibitors
• Monoamine Oxidase Inhibitors

Topics

• Alzheimer Disease (drug therapy)
• Cholinesterase Inhibitors (chemical synthesis, pharmacokinetics, therapeutic use)
• Humans
• Models, Molecular
• Monoamine Oxidase Inhibitors (chemical synthesis, pharmacokinetics, therapeutic use)